Download Dorsal spinal cord stimulation obtunds the capacity of intrathoracic

Am J Physiol Regul Integr Comp Physiol 297: R470–R477, 2009.
First published June 10, 2009; doi:10.1152/ajpregu.90821.2008.
Dorsal spinal cord stimulation obtunds the capacity of intrathoracic
extracardiac neurons to transduce myocardial ischemia
Jeffrey L. Ardell,1 René Cardinal,2 Michel Vermeulen,2 and J. Andrew Armour2
1
Department of Pharmacology, East Tennessee State University, James H. Quillen College of Medicine, Johnson City,
Tennessee; and 2Centre de recherche, Hôpital du Sacré-Cœur de Montréal, Montréal, Canada
Submitted 9 October 2008; accepted in final form 5 June 2009
cardiac pacing; ventricular ischemia; middle cervical ganglion neuron; cardiac nervous system; neurocardiology
electrical stimuli to the dorsal aspect of the T1–T4 thoracic spinal cord [spinal cord stimulation
(SCS)] can alleviate the symptoms associated with chronic
refractory angina pectoris (19, 23, 29, 32). SCS also stabilizes
ventricular electrical alterations that attend regional ventricular
ischemia (14), reduces the size of infarcts induced by transient
myocardial ischemia (37), and protects against ischemiainduced ventricular tachycardia/ventricular fibrillation in
animal models with chronic myocardial infarction and heart
failure (27).
Electrical neuromodulation impacts on the dynamic interactions among autonomic afferent and efferent neurons mediated
via, as yet poorly defined, spinal cord and peripheral neural
circuits (18, 20, 35, 43). Centrally, SCS reduces the release of
neuropeptides from cardiac nociceptive afferent neurons (17),
reduces intrasegmental and supraspinal transmission of cardiac
nociceptive information (20, 35), and increases the activity of
a subpopulation of thoracic sympathetic preganglionic efferent
neurons (17, 18). Peripherally, SCS reduces the activity gen-
DELIVERING HIGH-FREQUENCY
Address for reprint requests and other correspondence: Jeffrey L. Ardell,
Dept. of Pharmacology, East Tennessee State Univ., PO Box 70577, Johnson
City, TN 37614-0577 (e-mail: [email protected]).
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erated by intrinsic cardiac neurons by ⬃70% at baseline as well
as when they are activated by transient ventricular ischemia
(13, 21). Transection of the ansae subclavia eliminates the
suppressor effects of SCS on intrinsic cardiac neural activity,
indicating that responses are due primarily to the influence of
spinal cord neurons acting via the sympathetic nervous system
(21). The ability SCS to reduce infarct size secondary to
transient myocardial ischemia is blocked by prior adrenergic
blockade (37), likewise indicating a primary role for SCSmediated control of sympathetic efferent neurons regulating
the stressed heart.
Intrathoracic extracardiac neurons are in constant communication with intrinsic cardiac ones in the overall coordination
of regional cardiac indices (3, 11). Neurons in intrathoracic
extracardiac ganglia receive major inputs from the spinal cord
preganglionic neurons that are under the control of the intermediolateral cell column that, in turn, receives inputs from
spinal and supraspinal components of the cardiac neuronal
hierarchy (2, 20). Furthermore, inputs arising from spinal cord
neurons are known to exert influences on middle cervical
ganglion neurons involved in short-loop intrathoracic cardiocardiac reflexes (5, 6). It remains to be established whether
central neuronal inputs to the intrathoracic extracardiac nervous system influence the latter’s capacity to transduce the
cardiac milieu. Thus, the present experiments were designed
1) to determine whether spinal cord inputs influence the capacity of middle cervical ganglion neurons to transduce the
ventricular milieu and 2) to determine whether SCS influences
how these neurons respond to regional vs. global ventricular
stress, thereby impacting upon intrathoracic extracardiac sympathetic reflex function.
MATERIALS AND METHODS
Animal preparation. These experiments were performed in accordance with the guidelines for animal experimentation described in the
“Guiding Principles for Research Involving Animals and Human
Beings” (1), in accordance with the Guide to the Care and Use of
Experimental Animals set up by the Canadian Council on Animal
Care, and with the approval of the IACUC of the University of
Montreal.
Adult mongrel dogs (n ⫽ 10; 20 –25 kg) of either sex were
anesthetized with sodium thiopental (25 mg/kg iv, supplemented as
required), intubated, and maintained under positive-pressure ventilation. After surgery, anesthesia was maintained with ␣-chloralose (75
mg/kg iv bolus, with repeat doses of 12.5 mg/kg iv, as required).
Noxious stimuli were applied to a paw periodically to ascertain the
adequacy of anesthesia. Body temperature was maintained between
37.5 and 38.5°C by water-jacketed Micro-Temp heating units (Zimmer, Dover, OH). Fluid replacement (physiological saline) and
␣-chloralose were administered via a femoral vein catheter.
SCS. After placing the animal in the prone position, the epidural
space was entered with a Touhy needle via a small skin incision in the
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Ardell JL, Cardinal R, Vermeulen M, Armour JA. Dorsal spinal
cord stimulation obtunds the capacity of intrathoracic extracardiac
neurons to transduce myocardial ischemia. Am J Physiol Regul Integr
Comp Physiol 297: R470 –R477, 2009. First published June 10, 2009;
doi:10.1152/ajpregu.90821.2008.—Populations of intrathoracic extracardiac neurons transduce myocardial ischemia, thereby contributing
to sympathetic control of regional cardiac indices during such pathology. Our objective was to determine whether electrical neuromodulation using spinal cord stimulation (SCS) modulates such local reflex
control. In 10 anesthetized canines, middle cervical ganglion neurons
were identified that transduce the ventricular milieu. Their capacity to
transduce a global (rapid ventricular pacing) vs. regional (transient
regional ischemia) ventricular stress was tested before and during SCS
(50 Hz, 0.2 ms duration at 90% MT) applied to the dorsal aspect of the
T1 to T4 spinal cord. Rapid ventricular pacing and transient myocardial ischemia both activated cardiac-related middle cervical ganglion
neurons. SCS obtunded their capacity to reflexly respond to the
regional ventricular ischemia, but not rapid ventricular pacing. In
conclusion, spinal cord inputs to the intrathoracic extracardiac nervous system obtund the latter’s capacity to transduce regional ventricular ischemia, but not global cardiac stress. Given the substantial
body of literature indicating the adverse consequences of excessive
adrenergic neuronal excitation on cardiac function, these data delineate the intrathoracic extracardiac nervous system as a potential target
for neuromodulation therapy in minimizing such effects.
SCS BLUNTS MCG NEURONAL TRANSDUCTION OF MYOCARDIAL ISCHEMIA
AJP-Regul Integr Comp Physiol • VOL
cervical ganglion for hours using this methodology (6). Action potentials so identified were differentially amplified by means of a
Princeton Applied Research model 113 amplifier that had band pass
filters set at 300 Hz to 10 kHz and an amplification range of
⫻100 –500. The output of this device was further amplified (⫻50 –
200) and filtered (band width 100 Hz to 2 kHz) by means of an
optically isolated amplifier (Applied Microelectronics Institute, Halifax, NS, Canada). The amplified neuronal signals, together with the
cardiovascular signals, were digitized (Cambridge Electronics Design,
power 1401 data acquisition system) and analyzed using the Spike 2
software package (Cambridge Electronics Design). Ganglionic loci
were identified from which action potentials with signal-to-noise
ratios ⬎ 3:1 could be recorded. The activity generated by individual
neuronal somata was identified by the amplitude and configuration
(waveform recognition) of the recorded action potentials via the Spike
2 program. Using these techniques and criteria, action potentials
generated by individual cell bodies and/or dendrites rather than axons
of passage can be recorded for extended period of time (6, 11). As
such, once an active locus was identified the activity generated by its
spontaneously active neurons was studied throughout the duration of
the various protocols outlined below (cardiac stressors).
To identify middle cervical ganglion neurons that transduced the
left ventricular milieu, the activity generated by neurons within
various loci of the left middle cervical ganglion was recorded as
gentle mechanical stimuli (delivered by a saline-soaked cotton applicator) were applied for 2–3 s to various loci on the ventral and
ventrolateral surface of the left ventricle. It is known that most middle
cervical ganglion neurons that transduce the ventricular mechanical
milieu also transduce its local chemical milieu (12). Once a neuron
was identified that responded to repeat (⫻3) local mechanical deformation of epicardial regions adjacent to either the left anterior descending or circumflex coronary artery, its spontaneous activity was
recorded during 5–10 min control states to establish baseline values
for that index.
Cardiac stressors. The ventricles were then paced at 180 beats/min
for 5 min. After at least 5 min, the artery that perfused the identified
sensory field was occluded 3– 4 times. That is, the ventral descending
or circumflex coronary artery was occluded individually for 30 s,
depending on which vessels perfused its identified sensory field. At
least 5 min occurred between these interventions for preparation
stabilization. The order that these vessels were occluded varied among
animals. The order of applying these two protocols (ventricular pacing
vs. coronary artery occlusion) also varied among animals.
SCS protocol. To test the effects of activating the dorsal aspect of
the thoracic spinal cord (SCS) on the activity generated by cardiacrelated middle cervical ganglion neurons, in four preliminary animals
2-, 5-, 10-, and 15-min periods of SCS were studied in the absence of
stressors. SCS yielded similar neuronal activity changes at up to 15
min of SCS (27 ⫾ 23 impulses/min baseline to 38 ⫾ 27 impulses/min
at SCS termination, P ⫽ 0.36). To minimize the potential for longterm effects on neuronal activity post-SCS (13, 21), SCS was instituted in each experimental protocol for only 9 min thereafter. For the
global stress of rapid cardiac pacing, SCS was started 2 min before
and maintained for 2 min after the allocated 5-min periods of cardiac
pacing (total 9 min). These data were compared with those obtained
during 5-min of pacing alone. With respect to coronary artery occlusion (duration 30 s), occlusions were performed throughout the final
30 s of SCS (i.e., the occlusion and SCS terminated simultaneously)
and compared with the response to 30 s coronary artery occlusion by
itself. One hour elapsed between each protocol in which no interventions were instituted.
Data analysis. Spontaneous cardiodynamic fluctuations were minimal during control periods, heart rate varying ⬍ 5 beats/min, and
systolic pressure fluctuating ⬍ 5 mmHg. Thus, thresholds for classifying induced cardiovascular changes were chosen to be greater than
these ranges. Action potentials arising from a locus within each
middle cervical ganglion studied were characterized by means of their
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caudal dorsal thorax. A four-pole lead (Octrode; Advanced Neuromodulation Systems, Plano, TX) was advanced rostrally in the epidural space to the T1–T4 spinal cord level, utilizing anterior-posterior
fluoroscopy. The tip of the lead was positioned slightly to the left of
midline, according to current clinical practice (33). The most cranial
pole of the lead was positioned at the T1 level with the caudal pole at
the T3-T4 level. Electrical current was delivered via its rostral and
caudal poles to verify their functional position. Stimuli were delivered
via a stimulus isolation unit and constant current generator (model
SIU 5B; Grass Instruments, Quincy, MA) connected to a stimulator
(model S88 stimulator; Grass Instruments). Increasing stimulus intensity (with the rostral pole as cathode) to motor threshold (MT)
intensity induced muscle contractions in the proximal forepaw and
shoulder. Stimulation with the caudal pole as cathode at MT activated
thoracic paravertebral muscles, resulting in a twisting movement of
the trunk. Animals were rotated to the decubitus position and MT was
reestablished. In each experimental protocol, SCS was delivered for 9
min at 50 Hz, 200-␮s duration and at a current intensity of 90% MT
(range 0.19 and 0.78 mA; mean 0.43 mA). The rostral and caudal
poles were chosen as cathode and anode, respectively, according to
current clinical practice (32, 33). MT was checked periodically during
the experiment and did not vary significantly from initial levels.
Cardiovascular instrumentation. Heart rate was monitored via a
lead II ECG. Left ventricular chamber pressure was recorded via a
Millar catheter introduced into the left ventricular cavity via the right
femoral artery. A transthoracic incision exposed the heart and the left
middle cervical ganglia associated with the left thoracic vagosympathetic trunk. After opening the pericardial sac, two miniature solidstate pressure transducers (model P19; Konigsberg Instruments, Pasadena CA) were inserted into the left ventricle midwall in the
perfusion beds of the ventral descending and circumflex coronary
arteries. Aortic pressure was monitored via a Bentley Trantec model
800 transducer connected to a Cordis no. 6 catheter that was inserted
into the ascending aorta via a femoral artery. These cardiac indices
were monitored throughout the experiments via an eight-channel
rectilinear recorder (Nihon Kohden, Tokyo, Japan), digitized (power
1401; Cambridge Electronics Design), and analyzed (Spike 2, Cambridge Electronics Design) to determine mean hemodynamic values at
baseline and in response to each stressor.
Coronary artery occlusion. A 3-0 silk thread was placed around the
ventral descending coronary artery about 2 cm from its origin, distal
to the site of origin of the first major branch of that artery. Another silk
thread was placed around the circumflex coronary artery about 3 cm
from its origin, distal to the origin of its first major branch. These
threads were led through short polyethylene tubing segments for
subsequent snaring of each artery for 30 s. These occlusion sites were
chosen to obviate inducing too large a ventricular ischemic zone to
minimize subsequent ventricular arrhythmia induction.
Cardiac pacing protocol. Rapid ventricular pacing was performed
by delivering trains of super-threshold electrical stimuli at a rate of
180 pulses/min to the right ventricle for 5-min periods of time. This
was accomplished via bipolar electrodes that had been sutured to the
epicardium of the right ventricular outflow tract.
Middle cervical ganglion neuronal activity. The left middle cervical ganglion was identified and left in place, attached to surrounding
tissues to maintain its stability. The activity generated by neurons in
that ganglion was identified by using methods that have been described previously (6, 11). The recording microelectrode utilized had
a 250-␮m shank diameter, an exposed tip of 10 ␮m, and an impedance
of 9 –11 M⍀ at 1,000 Hz (model ME 25-10-2; Frederick Haer). The
indifferent electrode was attached to the mediastinum adjacent to that
middle cervical ganglion.
This ganglion was explored with the electrode tip placed from its
ventral surface to its underlying regions, such that the activity generated by neurons in various loci within that ganglion could be identified. Action potentials generated by the somata and/or dendrites of
individual neurons can be recorded from a locus within a middle
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SCS BLUNTS MCG NEURONAL TRANSDUCTION OF MYOCARDIAL ISCHEMIA
Table 1. Middle cervical ganglion neuronal activity
Ventricular Pacing
Control Stressors
Control
Intervention
Stressor with SCS
Control
SCS
SCS and intervention
36.7⫾28.1
79.8⫾47.5*
30.8⫾24.4
26.8⫾19.7
72.5⫾36.9*⫹
Coronary Artery Occlusion
41.5⫾35.6
111.0⫾61.4*
19.4⫾16.2
19.0⫾14.0
29.5⫾20.2#
differing configurations (waveform recognition) by employing the
Spike 2 program. Neuronal activity and cardiovascular indices recorded simultaneously before each intervention were compared with
those indices derived during each intervention, average activity representing the same population recorded throughout all interventions.
The grouped data so derived are expressed as means ⫾ SD. SigmaStat
RESULTS
Neuronal activity. Spontaneously active neurons identified
in one locus of each middle cervical ganglion were analyzed by
means of their unique action potential waveform configurations
(employing Spike-2 program). Only those that were activated
by gently mechanical stimuli applied to circumscribed epicardial loci on either the left ventricular ventral or lateral epicardial wall entered this study. As a consequence we were able to
identify in control states 3–5 neurons in an active ganglionic
locus. Collectively, neurons so identified generated about 40
impulses/min (Table 1). Although most neurons generated
activity throughout the cardiac cycle (Fig. 1), limited numbers
generated cardiac-related activity usually during ventricular
isovolumetric contraction (Fig. 2). Application of focal mechanical stimuli to these select ventricular epicardial loci activated these neurons two- to threefold, doing so similarly upon
repeat local mechanical stimulus application. Neurons so identified became the subject of subsequent investigation.
Fig. 1. Ventricular pacing modified cardiac-related middle cervical ganglion (MCG) neuronal activity. Top: rapid right ventricular pacing (RVP; initiated
throughout the RVP signal on upper trace) induced a fall in left ventricular pressure (LVP) while activating 3 neurons identified from raw MCG neuronal activity
(line below) by their unique action potential configurations (green, blue, and black vertical lines). Bottom: raster sweep plots of the action potentials generated
by these 3 neurons during consecutive cardiac cycles for 60 s during control states (baseline) and right ventricular pacing (RV pace). Time 0 is defined by QRS
onset. Activity increased during pacing, rapidly returning to control values once pacing ceased (cf, unit activity). Timing bars are located below each panel.
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Data are impulses/min; mean ⫾ SD; n ⫽ 10 dogs. Activity is the average of
3–5 identified ventricular middle cervical ganglion neurons generated per
animal. Neuronal activity increased during the rapid ventricular pacing, as well
as brief periods of regional ventricular ischemia. Spinal cord stimulation (SCS)
did not change neuronal activity overall; it suppressed neuronal responses to
regional ventricular ischemia but not those initiated by ventricular pacing.
*P ⱕ 0.02 control vs. intervention; ⫹P ⱕ 0.02 SCS vs. SCS and
intervention; #P ⱕ 0.01 intervention vs. SCS and intervention.
3.1 (Systat Software) with one-way ANOVA with post hoc comparisons (Holm-Sidak test) was used to test for differences within and
between groups. A significance of P ⬍ 0.05 was used.
SCS BLUNTS MCG NEURONAL TRANSDUCTION OF MYOCARDIAL ISCHEMIA
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Fig. 2. Spinal cord stimulation (SCS) modified the activity generated by MCG
neurons associated with left ventricular mechanosensory neurites. Lead II
electrocardiogram (ECG) (A) and left ventricular intramyocardial pressure (LV
IMP) (B) show QRS averaged values (dark line) recorded during each of 1,792
consecutive cardiac cycles (⫾ 1 SD thin lines). C: dots in the raster sweep plot
represent action potentials generated by 4 neurons recorded during the 1,792
cardiac cycles. This included activity recorded 2 min before (basal) and during
9 min of continuous SCS (SCS on ⫽ gray shaded area), as well as 4 min
following SCS (top of raster plot). The horizontal time 0 was set to the R wave
of the ECG. Activity increased as SCS persisted (gray zone in raster plot),
including after SCS termination (top of this plot C); increased activity demonstrated less phase locking to the cardiac cycle. D: cumulative index of all
action potentials recorded during these 1,792 consecutive cardiac cycles
demonstrating that activity was maximal during maximum local isovolumetric
dynamics of their receptor fields.
Rapid ventricular pacing. Cardiac pacing increased the activity generated by identified neurons, whether pacing was
tested for 1-min periods (Fig. 1) or for the 5-min periods used
to subsequently test the effects of SCS (Fig. 3). Pacing the
ventricles at 180 beats/min for 5 min enhanced neuronal
activity by ⬃117% (range of neuronal activity from 1.4 to 68.4
impulses/min at baseline to 4.8 to 128.1 impulses/min during
pace) (Table 1). All identified neurons responded with increased activity that occurred in excess of that related to
increasing the heart rate (50% increase rate; 120 beats/
min3180 beats/min). Furthermore, in some instances pacing
also initiated cyclic bursts of activity that persisted after terminating pacing (Fig. 3A). Left ventricular chamber and aortic
systolic pressures fell with pace onset. These indices gradually
returned to baseline values as pacing continued such that at the
AJP-Regul Integr Comp Physiol • VOL
DISCUSSION
In basal states, SCS is known to suppress the activity
generated by populations of intrinsic cardiac neurons (13, 21).
It also reduces the responsiveness of such neurons to regional
ventricular ischemia (13, 21). Data obtained from the current
study indicate that SCS modified populations of neuronal
somata located in intrathoracic extracardiac ganglia. Furthermore, it targets neurons in classical peripheral sympathetic
ganglia that in turn target cardiac indices. Although SCS did
not suppress overall basal activity generated by the subpopulations of intrathoracic sympathetic extracardiac neurons involved in transducing the ventricular milieu identified in this
study, it did obtund their capacity to transduce regional ventricular ischemia.
Reflex control of heart function is dependent upon complex
interactions within both peripheral and central neuronal elements of the cardiac neuronal hierarchy (2, 3, 20). Neuromodulation, targeted at various levels of the cardiac neuronal hierarchy, has the capacity to modify reflex function within the
hierarchy (17, 22) and the cardiomyocytes themselves (37).
Against the stress of acute myocardial ischemia, SCS reduces
electrical instability of the ventricle (27) and infarct size (37),
the later at least being dependent on modulation of adrenergic
nerve function (37). In animal models of reduced coronary
reserve, SCS mitigates the ST segment deviations associated
with chemical activation of intrathoracic adrenergic neurons
(14). SCS by itself (18), or in combination with coronary artery
occlusion (17), increases cFos expression within subpopula297 • AUGUST 2009 •
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end of pacing (when neuronal activity was quantified) aortic
pressure (128 ⫾ 7/100 ⫾ 6 mmHg) was comparable to that of
control states (130 ⫾ 7/100 ⫾ 6 mmHg).
Coronary artery occlusion. The activity generated by identified neurons increased during transient occlusion of either the
left anterior descending or circumflex coronary artery, depending on whether the location of the mechanosensory field
associated with identified neurons in individual animals was
perfused by one or the other artery (Fig. 4A; Table 1). Repeated
artery occlusion induced similar neuronal responses. Intramyocardial systolic pressure in the nonoccluded ventricular zone
remained unchanged overall (106 ⫾ 11 to 98 ⫾ 8 mmHg; not
significant); corresponding intramyocardial pressures in the
risk zone fell ⬃18% during the transient coronary occlusion.
Transient coronary artery occlusion did not alter heart rate
(121 ⫾ 8 to 120 ⫾ 10 beats/min) or aortic pressure (130 ⫾
10/98 ⫾ 7 to 130 ⫾ 11/95 ⫾ 8 mmHg) overall.
SCS. Nine minutes of SCS did not alter heart rate, left
ventricular chamber pressure, or aortic pressure overall (data
not shown). SCS did not change neuronal activity overall
(Table 1), even though in some instances activity of a few
neurons was changed (Fig. 2).
Stressors in the presence of SCS. When ventricular pacing
was instituted in the presence of SCS, the enhancement of
neuronal activity was similar to that which had occurred during
that intervention in the absence of SCS (Table 1). However, in
two of the animals, SCS reduced the period of time that pacing
modified neuronal activity (Fig. 3). In contrast, regional ventricular ischemia no longer enhanced the activity generated by
identified middle cervical ganglion neurons when instituted in
the presence of SCS (Fig. 4; Table 1).
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SCS BLUNTS MCG NEURONAL TRANSDUCTION OF MYOCARDIAL ISCHEMIA
tions of high thoracic sympathetic preganglionic neurons. In
the current study, while the average response of middle cervical ganglia neurons to SCS did not change over the stimulation
times evaluated (up to 15 min), a subset of these neurons were
augmented, an effect that outlived the stimulation (Fig. 2).
Considering the heterogeneous neuroanatomical organization
of the extracardiac intrathoracic autonomic ganglia (24, 25),
including afferent, efferent, and local circuit neurons, it is not
unexpected that the integrated reflex response to stressors is
partially reflective of the characteristics of their imposed afferent and efferent neuronal inputs. As the vast majority
(⬃70%) of neurons in the middle cervical ganglia that respond
to local epicardial mechanical deformation or chemical stimuli
are local circuit in nature (5, 6), presumably this population of
polymodal neurons represented the principal neuronal population evaluated in this study. Presumably that is, in part, why
most identified neurons were not directly activated by SCS.
Moreover, SCS exerts its cardioprotective effects (14, 27, 37)
without interfering with the direct flow-through pre- to postAJP-Regul Integr Comp Physiol • VOL
ganglionic efferent neuronal projections (34). We have proposed instead that SCS exerts it cardioprotective effects, in
part, by modulating reflex processing within intrathoracic ganglia (13, 14).
Significant subpopulations of neurons within intrathoracic
extracardiac and intrinsic cardiac ganglia perform a major
processing function: interconnecting neurons located within
individual or separate intrathoracic ganglia. Local circuit neurons perform this function (3, 8, 10, 41). This neuron population forms the substrate for the processing of cardiovascular
afferent information within peripheral autonomic ganglia, even
when such ganglia are disconnected from the influence of
central neurons (4, 7). Local circuit neurons transduce cardiovascular afferent information reflexly to modulate the sympathetic and parasympathetic efferent outflows to cardiac effector
sites (11). This population also receives significant descending
inputs from central neurons (9, 28, 41). These neurons are
crucial for overall information processing within the intrathoracic nervous system and, as such, represent a principal mod297 • AUGUST 2009 •
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Fig. 3. A: rapid ventricular pacing (horizontal bar below) increased neuronal activity. A maximum of 5 identified middle cervical ganglion neurons were recorded
that generated increased (cyclic bursts) activity during pacing, something that persisted for some time after discontinuing pacing. B: 9 min of SCS (started 2 min
prior to pacing; horizontal bar below) induced a lesser response to pacing (lowest horizontal bar) and one that extinguished soon after discontinuing SCS. In each
panel, from above downward, are: neuronal activity averaged over 5-s sequential intervals, discriminated neuronal activity (activated neurons), and
intramyocardial pressure (LV IMP) recorded adjacent to the identified sensory neurite field. The horizontal bar below represents SCS application time (applied
2 min before and continuing for 2 min after pacing).
SCS BLUNTS MCG NEURONAL TRANSDUCTION OF MYOCARDIAL ISCHEMIA
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ulator of the final efferent neuronal outflows to different
cardiac regions (3, 10). We hypothesize that the population of
local circuit neurons represents the preferential target for SCSderived neuromodulation and that such inhibition limits excessive reflex responses of the cardiac nervous system responding
to the stress of acute myocardial ischemia. It is known that the
inputs so activated in the spinal cord project to intrathoracic
extracardiac neurons via the ansae (8, 9). Whether this occurs
via the efferent or afferent axonal projections from the spinal
cord remains to be explored, although the former is the most
likely occurrence. In conjunction with SCS-induced effects to
increase myocyte resistance to ischemic stress (14, 37), we
propose that within the risk zone the supply/demand imbalance
is thereby reduced, as is sensory activation within that zone and
this is fundamental to the clinical experience of angina relief
associated with SCS neuromodulation therapy (32).
Middle cervical ganglion neurons involved in transducing
the cardiac mechanical and/or chemical milieu (11) become
AJP-Regul Integr Comp Physiol • VOL
excited by global cardiac stresses such as that attending rapid
ventricular pacing. Such an intervention alters the mechanical
and chemical milieu of both ventricles, thereby enhancing
sensory inputs derived from multiple cardiac afferent neurons
that influence populations of middle cervical cardiac neurons
(6) such that they become activated (Table 1). In preliminary
experiments in which relatively short-term ventricular pacing was tested, activity increased soon after initiating pacing
(Fig. 1). These data indicate that cardiac pacing influences
the intrathoracic cardiac nervous system, an influence that
extinguishes with time once pacing is terminated (Figs. 1
and 3).
The present study indicated that SCS is ineffective at overcoming excessive sensory inputs arising from a global cardiac
stress such as that initiated by rapid ventricular pacing. In
accord with that observation, such spinal cord inputs are
likewise ineffectual in reducing pacing-induced ST segment
deviations in animal models with reduced coronary reserve
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Fig. 4. Effects of left anterior descending coronary artery occlusion (30-s duration; horizontal bars below each panel) on middle cervical ganglion neuronal
activity before (Pre-SCS) (A) and during (B) SCS. The time scales of these 2 records differ in order to emphasize the lack of long-term effects of ischemia after
SCS. Neuronal activity and activated neuron traces are as defined in Fig 1.
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SCS BLUNTS MCG NEURONAL TRANSDUCTION OF MYOCARDIAL ISCHEMIA
Perspectives and Significance
The reflex response of the cardiac neuronal hierarchy to
imposed cardiac stress is a primary determinant of resultant
cardiac responses. During acute myocardial ischemia, individuals that exhibit excessive and imbalanced sympathoexcitation
are at increased risk for sudden cardiac death and/or progression into congestive heart failure (16, 30, 40). While ␤-adrenergic blockade has documented efficacy to reduce adverse
consequences of such cardiopathology (16, 38), there are
multiple untoward effects associated with its use (42). The
cardiac neuronal hierarchy has emerged as a novel therapeutic
target for managing cardiac disease via pharmacological (36,
39), physical (26, 31), and/or electrical (15, 37, 43) means to
target specific nexus points within the associated neural networks. That SCS blunts/stabilizes intrathoracic extracardiac
neuronal transduction of regional ventricular ischemia supports
the concept that SCS imparts its cardioprotective effects on
cardiac electrical stability (27) and myocyte viability (37) via
multiple intrathoracic neuronal populations.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the technical assistance of Caroline
Bouchard.
GRANTS
This study was supported by the Canada Institutes of Health Research (to
R. Cardinal and J. A. Armour), the Quebec Heart and Stroke Foundation (to
J. A. Armour and R. Cardinal), and the National Heart, Lung, and Blood
Institute Grant HL-71830 (to J. L. Ardell).
AJP-Regul Integr Comp Physiol • VOL
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(14). This may reflect an overriding direct local metabolic
effect of cardiac pacing on the interstitial milieu and resultant
global increase in cardiac afferent neuronal transduction.
Against such pacing-induced afferent input barrage, the capacity for higher centers to modulate intrathoracic reflex processing may be limited. However, while maximal reflex responses within the middle cervical ganglia neurons to an
imposed pacing stress is maintained during SCS (Table 1),
the duration of sympathoexcitation can in some instances be
truncated (Fig. 3).
Regional ventricular ischemia creates boundary conditions
whereby more limited ventricular sensory neurite fields are
affected relative to the surrounding interstitium. Such a cardiac
substrate would initiate differential sensory inputs to middle
cervical ganglion cardiac neurons to enhance the activity of
intrathoracic extracardiac local circuit neurons (3, 6). Differential transduction of regional boundary conditions likely represents a substantially different neuronal substrate on which
descending neuronal projections might act, especially when
considering the processing elements within the intrathoracic
extracardiac ganglia, the local circuit neurons (12). Presumably
that is why the enhancement of neuronal activity subsequent to
ischemia transduction rendered this population more sensitive
to SCS. Taken together, these data indicate that spinal cord
inputs to the intrathoracic extracardiac nervous system are
capable of altering its capacity to transduce the ischemic
myocardium by primarily targeting neuronal processing elements within its ganglia, the local circuit neurons.
SCS BLUNTS MCG NEURONAL TRANSDUCTION OF MYOCARDIAL ISCHEMIA
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